Mitochondrial regulation of insulin production in rat pancreatic islets

G. Leibowitz*, M. Z. Khaldi, A. Shauer, M. Parnes, A. I. Oprescu, E. Cerasi, J. C. Jonas, N. Kaiser

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Aims/hypothesis: The study was designed to identify the key metabolic signals of glucose-stimulated proinsulin gene transcription and translation, focusing on the mechanism of succinate stimulation of insulin production. Methods: Wistar rat islets were incubated in 3.3 mmol/l glucose with and without esters of different mitochondrial metabolites or with 16.7 mmol/l glucose. Proinsulin biosynthesis was analysed by tritiated leucine incorporation into newly synthesised proinsulin. Preproinsulin gene transcription was evaluated following transduction with adenoviral vectors expressing the luciferase reporter gene under the control of the rat I preproinsulin promoter. Steady-state preproinsulin mRNA was determined using relative quantitative PCR. The mitochondrial membrane potential was measured by microspectrofluorimetry using rhodamine-123. Results: Succinic acid monomethyl ester, but not other mitochondrial metabolites, stimulated preproinsulin gene transcription and translation. Similarly to glucose, succinate increased specific preproinsulin gene transcription and biosynthesis. The inhibitor of succinate dehydrogenase (SDH), 3-nitropropionate, abolished glucose- and succinate-stimulated mitochondrial membrane hyperpolarisation and proinsulin biosynthesis, indicating that stimulation of proinsulin translation depends on SDH activity. Partial inhibition of SDH activity by exposure to fumaric acid monomethyl ester abolished the stimulation of preproinsulin gene transcription, but only partially inhibited the stimulation of proinsulin biosynthesis by glucose and succinate, suggesting that SDH activity is particularly important for the transcriptional response to glucose. Conclusions/interpretation: Succinate is a key metabolic mediator of glucose-stimulated preproinsulin gene transcription and translation. Moreover, succinate stimulation of insulin production depends on its metabolism via SDH. The differential effect of fumarate on preproinsulin gene transcription and translation suggests that these processes have different sensitivities to metabolic signals.

Original languageAmerican English
Pages (from-to)1549-1559
Number of pages11
JournalDiabetologia
Volume48
Issue number8
DOIs
StatePublished - Aug 2005
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements This work was supported in part by grants from Russell Berrie Foundation and D-Cure, Diabetes Care in Israel, the Israel Science Foundation and the Israel Ministry of Health (to G. Leibowitz and N. Kaiser) and by grant 1.5.182.04 from the Fonds National de la Recherche Scientifique (to J.-C. Jonas). J.-C. Jonas is Senior Research Associate from the Fonds National de la Recherche Scientifique (Belgium). The authors are grateful to Yafa Ariav for dedicated technical assistance.

Keywords

  • Insulin secretion
  • Islets
  • Mitochondria
  • Preproinsulin gene transcription
  • Proinsulin biosynthesis
  • Rat
  • Succinate
  • Succinate dehydrogenase

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